First Encounter: How Pathogens Compromise Epithelial Transport

Karl Kunzelmann and Brendan McMorran

You might find this additional info useful... This article cites 48 articles, 29 of which can be accessed free at: http://physiologyonline.physiology.org/content/19/5/240.full.html#ref-list-1 This article has been cited by 2 other HighWire hosted articles Pseudomonas Lipopolysaccharide Accelerates Wound Repair via Activation of a Novel Epithelial Cell Signaling Cascade Jonathan L. Koff, Matt X. G. Shao, Suil Kim, Iris F. Ueki and Jay A. Nadel J Immunol, December 15, 2006; 177 (12): 8693-8700. [Abstract] [Full Text] [PDF] The emerging role of PDZ adapter proteins for regulation of intestinal ion transport G. Lamprecht and U. Seidler Am J Physiol Gastrointest Liver Physiol, November 1, 2006; 291 (5): G766-G777. [Abstract] [Full Text] [PDF] Updated information and services including high resolution figures, can be found at: http://physiologyonline.physiology.org/content/19/5/240.full.html Additional material and information about Physiology can be found at: http://www.the-aps.org/publications/physiol Physiology 19:240-244, 2004. doi:10.1152/physiol.00015.2004

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Physiology (formerly published as News in Physiological Science) publishes brief review articles on major physiological developments. It is published bimonthly in February, April, June, August, October, and December by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2004 by the American Physiological Society. ISSN: 1548-9213, ESSN: 1548-9221. Visit our website at http://www.the-aps.org/.

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PHYSIOLOGY 19: 240244, 2004; 10.1152/physiol.00015.2004

First Encounter: How Pathogens Compromise Epithelial Transport

Pathogenic organisms trigger numerous signaling pathways that ultimately lead to drastic changes in physiological functions. Apart from altering structure and function of the epithelial tight junction barrier and activating inflammatory cascades, they induce changes in fluid and electrolyte transport. Pathogens do so by activating or by inhibiting ion channels and transporters, and the result might be to their benefit or to their disadvantage.

Karl Kunzelmann
1

Institut fr Physiologie, Universitt Regensburg, D-93053 Regensburg, Germany uqkkunze@mailbox.uq.edu.au

Brendan McMorran
Institute of Molecular Bioscience, The University of Queensland, St. Lucia, 4072 Queensland, Australia

Pathogens alter epithelial structure and function Our body is constantly challenged by pathogenic organisms, such as bacteria, viruses, and fungi (FIGURE 1). Most of these pathogens must overcome an epithelial cell barrier to establish an infection. The major portals of pathogen entry are the epithelial skin layer and the epithelial layers coating the gastrointestinal, respiratory, and urogenital tracts. Although both tissues clearly show transport function, the skin is complex with multiple keratinized cell layers, whereas internal surfaces are lined by only a single layer of highly polarized epithelial cells. These cells have distinct luminal and basolateral membranes composed of different phospholipids. They contain different sets of receptors and transport proteins and are electrically separated by tight junctions (TJ). Epithelia are not merely static barriers to the external environment. There is a rather complex and dynamic cross-talk between pathogens and the epithelium (2, 6, 24). Pathogen-host interactions are known to result in perturbations of the structure and function of TJ, induction of inflammatory responses, and other alterations in epithelial cell function (FIGURE 1). More recent evidence also indicates that fluid and electrolyte transport processes are affected, either specifically or as a consequence of altered cell function. Examples describing secretion-altering activities involve both pathogen-derived and pathogen-driven, host-derived molecules as well as direct pathogen bind240

ing to epithelial cells. In this short overview we will focus on the rapid effects that pathogens exert on epithelial electrolyte transport. This is a new and exciting field that may turn out to be of large pathophysiological relevance. Pathogen-host cell contact: host recognition and pathogen attack Pathogens may affect epithelial properties by means of secreted toxins, through directly pathogen-induced changes in enzyme function or protein expression, and through attachment to the cell membrane (FIGURE 2). In fact, attachment is regarded as the first contact of the intruder with the epithelium. Epithelial cells possess an array of cell surface molecules that monitor epithelial surfaces by binding various pathogen epitopes and eliciting cellular responses (FIGURE 2). The Toll-like receptor (TLR) family member TLR-4 and CD14, for example, cooperate in the recognition of the gram-negative bacterial cell wall component lipopolysaccharide (LPS) (48). Interestingly, the respiratory syncytial virus (RSV) also uses these receptors during transcytosis (48). The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) ion channel may also act as a pathogen receptor for Pseudomonas aeruginosa and Salmonella typhi uptake (36). However, this issue has been discussed controversially. Although some studies show attachment of P. aeruginosa to CFTR and its reduced clearance in CF airways, others do not find attachment to CFTR but rather to asialyated gly-

colipid (asialoGM1), which is upregulated in CF (9, 21, 25, 37). Thus undersialylated proteins, abundant in membranes of CF cells, serve as binding sites for S. aureus and P. aeruginosa (9, 21). Pneumococcus spp. translocate from the apical to basal cell surface via interactions with platelet-activating factor receptors and immunoglobulin receptors via choline-binding proteins (24). Some bacteria provide their own receptors, like enteropathogenic Escherichia coli, which are inserted into the host cell membrane. Others use basolaterally located host cell membrane proteins such as E-cadherin (Shigella, Listeria) or -integrins (Yersinia) (24). These and other host membrane components (mannose receptor, proteoglycans, glycosaminoglycans, vitronectin, and CD66 proteins) may serve as bacterial attachment factors and initiate clathrinmediated endocytosis of obligate intracellular parasites such as Chlamydia. Fungi and viruses are recognized by a number of protein-based receptors like TLRs but also bind to a variety of carbohydrate molecules that are very abundant at the epithelial cell apical surface. The common blood group antigen glycosphingolipids are important in Candida albicans infection (4). Viruses bind to sialic acid-containing oligosaccharides and heparan sulfate proteoglycans. Fungal and viral pathogens also interact with common glycoconjugates on eukaryotic membranes such as lectins as well as receptors located on the extracellular matrix formed by fibronectin or laminin (unpublished observations).

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PATHOGEN

Bacterium

Fungus

Virus

TIGHT JUNCTION

ELECTROLYTE TRANSPORT

INFLAMMATION

Toxin Pathogen Leakage Actomyosin dysruption Cl PKC Protease Luminal Basolateral Luminal Na+ Pathogen cAMP cGMP Ca2+ PKC

Pathogen

Luminal Cytokines (IL-2IL-10, TNF , IFN ) Adhesion molecules, MHC II

Basolateral

K+

IL-8

Neutrophil

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Basolateral

5' AMP

Apoptosis

FIGURE 1. Structure and function of tight junctions are altered by direct pathogen binding to tight junction proteins, PKC, and protease-mediated disruption of actomyosin
Left: released inflammatory mediators change electrolyte transport directly or stimulate submucosal nerve cells or immune cells (mucosa-associated lymphatic tissue) to release mediators that then change epithelial ion transport. Middle: pathogens bind to the host cell membrane and activate intracellular second messengers (cAMP, cGMP, Ca2+, PKC). Second messengers change the activity of ion channels, or pathogens may release toxins that activate one or several of these second messenger pathways or directly manipulate the activity of ion channels. Right: bacterial adherence triggers expression and secretion of inflammatory cytokines, adhesion molecules, and major histocompatability complex (MHC) class II molecules. Neutrophils are chemoattracted to the luminal side of the epithelium, release superoxide, induce cell damage, and activate secretion by release of AMP. Typically, MAPK are activated as well as PKC. The transcription factors NF- B and AP-1 as well as inducible nitric oxide (NO) synthase (iNOS) are activated. MAPK PKC Tryptase NF B AP-1 PGE2 TNF IFN IL-1 NO iNOS Cl Na+ PAR2

Inflammatory mediators PGE2 TNF IFN IL-1 NO

Pathogen-driven changes in cell signaling Epithelial receptors are a key feature in initiation of host innate immunity. As a paradigm, pathogen binding and/or internalization results in cell signaling changes, secretion of chemokines, and secretion of host defense molecules, in turn attracting immune cells that release an array of microbiocidal compounds and additional cell regulators (FIGURE 1). Both physical pathogen-cell interactions and the resulting changes in intra- and extracellular compounds have profound influences on epithelial cell fluid and electrolyte transport. In early observations, purified Pseudomonas rhamnolipids as well as LPS from Klebsiella

pneumoniae were found to inhibit epithelial Na+ absorption through binding to TLR-2 or TLR-4, respectively (15, 49). Thus it will be interesting to determine if membrane attachment pathogens such as P. aeruginosa will effect Na+ absorption by the epithelial Na+ channel ENaC. P. aeruginosa has been shown recently in our experiments with isolated perfused mouse tracheal epithelium and previously in studies with bovine trachea and dog bronchial epithelia to induce changes in fluid transport, probably by inhibition of ENaC (11, 45). Pathogen attachment triggers a multitude of intracellular signaling pathways, most notably those involving MAPKs, phosphatidylinositol 3-kinase, protein kin-

ase C (PKC), intracellular calcium, and nuclear factor- B (NF- B). It seems obvious that several of these messengers, besides other cellular effects, will also affect the activity of proteins mediating ion transport (FIGURE 2). P. aeruginosa activates Ca2+-dependent MAPKs in airway epithelial cells via binding to asialoGM1 receptors (41). Activation of this pathway also results in an inhibition of epithelial Na+ absorption (11, 45) and an increase in mucin production (11, 32, 33, 45). More recent studies indicate that binding by this CF pathogen elicits ATP release and autocrine activation of purinergic nucleotide receptors (33). Experiments in our laboratory indicate that asialoGM1-mediated
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TOXINS

Luminal

Basolateral

Cholera toxin (CTX) E. coli LT and ST Clostridium ToxA,B Pathogen-derived NO E. coli ST V. parahaemolyticus TDH Salmonella SopB Rotavirus NSP4
PATHOGEN INDUCED

cAMP cGMP Ca2+ PKC IP4 Pathogen iNOS PGHS NO PG Gal-1R

Salmonella Shigella E. coli

PATHOGEN ATTACHMENT

mouse airways by a PKC-dependent mechanism (26). Similar observations were made in mouse airways exposed to the paramyxovirus member Sendai virus (27). Further exciting discoveries may be expected in future for other hemagglutinating viruses, because lectin binding has been demonstrated to cause changes in epithelial ion transport (13, 29). The reduced NaCl absorption is likely to contribute to accumulation of fluid in the respiratory tract during viral airway infection. Pathogen-driven cell-secreted molecules

TLR/CD14 Bacterium Glycophospholipids PAF/Cholin BP Mannose receptor Proteoglycans Virus Pathogensecreted receptor MAPK PI3K NF B Ca2+ PKC

E-cadherin -integrin

Fibronectin Laminin

Fungus

FIGURE 2. Pathogens change epithelial ion transport by secreting toxins, activating enzymes, and attaching to the host cell membrane
Toxins are subdivided according to their effects on intracellular messengers cAMP, cGMP, or Ca2+/PKC/inositol 1,4,5,6-tetrabisphosphate (IP4). Pathogens induce expression of secretory galanin receptors (Gal-1R) and prostaglandin synthase (PGHS) or activate iNOS. Pathogens attach to a variety of host cell receptors or to the extracellular matrix, thereby activating intracellular second messengers and transcription factors. LT and ST, heat-labile and heat-stable enterotoxin; TLR, Toll-like receptor; PAF, platelet-activating factor; PBP binding protein; PI3K, phosphatidylinositol 3kinase; TDH, thermolabile hemosylin; NSP, nonstructural protein.

release of ATP induces the hydrolysis of intracellular phosphoinositol 4,5bisphosphate and, as a direct consequence, inhibition of ENaC (1). Thus pathogens affecting the activity of epithelial Na+ channels are likely to reduce epithelial absorption. In contrast, pathogens that change the concentration of intracellular second messengers by producing toxins or by binding to membrane receptors may induce secretory transport. Both transport proteins, the CFTR Cl channel and the Na+/H+ exchanger NHE3, are regulated by cAMP, a messenger frequently changed during infection with pathogens. Thus Cl secretion will be induced by cAMP-dependent activation of CFTR Cl channels, whereas electroneutral NaCl absorption by NHE3 will be reduced.
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The electrically sealed nature of epithelia may also be breached by disruption of the TJ. Pathogens target TJ integrity by direct binding or by activating cell PKC and proteases, which lead to redistribution and degradation of TJ proteins as found in ulcerative colitis (2, 28, 42) (FIGURE 1). Viral-epithelial interactions also have a number of effects on cell signaling (FIGURE 2), and recent studies raise the possibility that Na+ transport is also affected. Respiratory viruses such as rhinovirus have been reported to activate p38 MAPK (16), PKC is activated during RSV infection (16, 34), and the hemagglutinating influenza virus activates the Raf/MEK/ERK and PKC cascades (26, 38). This latter orthomyxovirus was shown to inhibit amiloride-sensitive Na+ absorption in

A major epithelial response to pathogen contact is the activation of an inflammatory cascade. Pathogen adherence triggers expression and secretion of a typical composition of cytokines, adhesion molecules, and major histocompatibility complex class II molecules (FIGURE 1). Neutrophils are attracted to the luminal side of the epithelium by cytokines like IL8. Inflammatory cells release superoxide and induce cell damage and the release of AMP, which is converted to adenosine and binds to A2b receptors. Activation of these receptors increases intracellular cAMP and activates secretory ion channels (2, 28). Typically several MAPKs are activated during inflammation, including ERK, JNK, and p38 as well as PKC, leading to the activation of the transcription factors NF- B and AP-1. As well as exerting proapoptotic activity on epithelial cells (23), NF- B and AP-1 also induce the production and release of cytokines such as TNF- , IL6, and IL-8 and the inflammatory mediator nitric oxide (NO) through upregulation of inducible NO synthase expression. Released inflammatory mediators activate electrolyte secretion in intestinal and airway epithelial cells (3, 28, 31, 43, 46). For example, ENaC-mediated Na+ absorption is inhibited by TNF- and NO (14, 18, 22). Other molecules are released by epithelia on exposure to various bacteria, fungi, and even protozoa with potent secretagogue activity, including the secretory neuropeptide galanin and prostaglandins.

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Interestingly, Saccharomyces boulardii-conditioned medium has been demonstrated to modulate secretagogue-induced cAMP and Ca2+dependent Cl secretion in colonic epithelial cells (7, 8). This may have applications for the prevention and treatment of intestinal infections and diarrhea. Similarly, cytokines released during inflammatory cholangiopathies trigger NO release, inhibiting adenylate cyclase and thus cAMP-depend ent HCO3 and Cl secretion. This process may largely contribute to biliary cholestasis (44). Alternatively, inflammatory mediators may stimulate submucosal nerve or immune cells to release proteases such as tryptase, which then stimulate type 2 protease-activated receptors located on epithelial cells and enteric nerves (28) (FIGURE 1). Several pathogens such as Salmonella and E. coli affect TJ integrity in parallel, causing release of inflammatory mediators and altering ion transport. Moreover, these events do not occur independently of each other. It is obvious that TJ barrier damage will distort the vectorial ion transport and that inflammatory mediators will affect a broad range of cellular second messengers (2). Pathogen-derived effects on epithelial ion transport Many pathogenic bacteria produce molecules with highly toxic activities against host cells. Many of these toxins not only directly affect the viability and integrity of the epithelium but also exert specific changes on cellular ion transport (FIGURE 3). Prominent examples are the toxins from Vibrio cholera (CTX) and the heat labile (LT) and heat stable (ST) enterotoxins from E. coli (FIGURE 2). These toxins can act through different mechanisms to induce Cl secretion. CTX and LT stimulate Gs proteins via ADP-ribosylation and activation of adenylate cyclase, whereas ST activates guanylate cyclase, resulting in activation of CFTR, basolateral cAMP/cGMPdependent KCNQ/KCNE K+ channels, and the basolateral NKCC1 cotransporter (2, 28) (FIGURE 3). Similar cellular mechanisms are exploited by Klebsiella pneumoniae and Yersinia enterocolitica toxins (17, 40). The SopB toxin from Salmonella not only acts on the cytoskeleton but also increases intracellular inositol 1,4,5,6-tetrabisphosphate, which activates Ca2+-activated Cl channels during cell invasion (12). The thermostable direct hemolysin from Vibrio parahaemolyticus, a worldwide cause of gastroenteritis, is another example of a toxin that activates Ca2+-dependent Cl secretion (39). A clinically relevant, nonbacterial example is the enterotoxin NSP4 from Rotavirus that activates phospholipase C and intracellular Ca2+ and thus induces Cl secretion (10, 47). Ca2+-activated Cl secretion is due to luminal Ca2+-activated Cl channels of unknown identity and parallel activation of basolateral Ca2+-activated SK4 K+ channels (FIGURE 3). In addition to ion transport, toxins may also target the absorption of substrates such as glucose and amino acids, exemplified by the Rotavirus toxin NSP4 (19). Summary What are the consequences of pathogen-induced changes in epitheLuminal H+ NHE3 HCO3 NSP4 SGLT1 PIP2 cAMP Na+ ENaC PKC NO TNF NKCC1 Cl CFTR cAMP cGMP PKC Ca2+ IP4 NO Na+ K+ 2Cl K+ KCNQ/KCNE K+ SK4 S Na+ NHERF Na+ Cl cAMP

lial fluid and ion transport, and who benefits? From the examples described to date, the vast majority of effects result in increased apical fluid secretion by epithelial cells and are rapid, occurring within minutes of pathogen interaction. This may be advantageous to both host and pathogen. Increased fluid secretion may enhance the flushing effect in the airway, intestine, and urogenital tracts, clearing noxious compounds and pathogens (20). The lung especially relies on apical fluid homeostasis for its defense, as illustrated by the high susceptibility to infection experienced in CF. Thus pathogen-stimulated apical electrolyte and fluid responses may represent an important but poorly understood host defense mechanism. On the other side of the coin, increased apical secretion may enhance the invading pathogens motility and host defense evasion and may increase potential for transmission to additional hosts. Future work should clarify who profits from the change in epithelial transport. T

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Basolateral

FIGURE 3. Regulation of epithelial electrolyte and substrate transport

Electroneutral absorption by the Na+/H+ exchanger NHE3 is inhibited by cAMP, whereas anion exchange is activated. The Rotavirus toxin NSP4 inhibits the Na+-glucose transporter SGLT1. Na+ absorption by the epithelial Na+ channel ENaC is activated by phosphoinositol 4,5-bisphosphate (PIP2) and cAMP but is inhibited by PKC, NO, and TNF- . Cl secretion by the cystic fibrosis transmembrane conductance regulator (CFTR) is activated by cAMP, cGMP, and PKC, and NO is maintained by basolateral NKCC1 as well as KCNQ/KCNE K+ channels. Ca2+-activated Cl secretion (Ca2+, IP4) occurs via a different class of luminal Cl channels, along with parallel activation of basolateral SK4 K+ channels.

Cl

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This work is continuously supported by Else Krner-Fresenius Stiftung and Mukoviszidose e.V. B. McMorran is supported by the National Health and Medical Research Council of Australia.
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